Brain tumors are major causes of morbidity and mortality, particularly among young people. Moreover, their incidence appears to be increasing for unknown reasons. The causes of brain tumors are not known, although radiation, pollutants, and electromagnetic fields are suspected. Most brain tumors are inoperable; even for those brain tumors that are operable, operations to remove them are extremely difficult and delicate and frequently leave neurological deficits. There is a need for more efficient chemotherapeutic treatment of brain tumors.
One possible avenue of treatment for brain tumors, as yet little explored, involves intracerebral neural grafting of cells that produce anti-cancer agents. This may offer the advantage of averting repeated drug administration while also avoiding the drug delivery complications posed by the blood-brain barrier. (Rosenstein, Science 235:772-774 (1987)).
As these critical factors have become recognized and optimized, intracerebral grafting has become a valid and reliable tool for neurobiologists in the study of CNS function and potentially for clinicians for the design of therapies of CNS disease, including brain tumors.
In parallel to the progress in neurobiology during the past several decades, advances in the understanding of molecular biology and the development of sophisticated molecular genetic tools have provided new insights into human disease in general. As a result, medical scientists and geneticists have developed a profound understanding of many human diseases at the biochemical and genetic levels. The normal and abnormal biochemical features of many human genetic diseases have become understood, the relevant genes have been isolated and characterized, and early model systems have been developed for the introduction of functional wild-type genes into mutant cells to correct a disease phenotype. (Anderson, Science 226:401-409 (1984)). The extension of this approach to whole animals, that is, the correction of a disease phenotype in vivo through the use of the functional gene as a pharmacologic agent, has come to be called "gene therapy". (Friedmann et al., Science 175:949-955 (1972); Friedmann, Gene Therapy Fact and Fiction, Cold Spring Harbor Laboratory, New York (1983)). Gene therapy is based on the assumption that the correction of a disease phenotype can be accomplished either by modification of the expression of a resident mutant gene or the introduction of new genetic information into defective or damaged cells or organs in vivo.
Procedures for in vivo gene therapy have been described. See, e.g., Rosenberg et al., Science 242:1575-1578 (1988), and Wolff et al., Proc. Natl. Acad. Sci. U.S.A. 86:9011-9014 (1989), both incorporated herein by this reference, as well as co-pending U.S. patent application Ser. No. 07/285,196 by Gage, entitled "Method of Grafting Genetically Modified Cells to Treat Defects, Disease or Damage of the Central Nervous System," filed Dec. 15, 1988, and incorporated herein by this reference.
The anti-viral agents acyclovir (9-((2-hydroxyethoxy)methyl)guanine) and ganciclovir (9-((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl) guanine) are efficient for preventing the replication of herpes virus, as the thymidine kinase coded for by the herpes virus genome and produced in cells infected by the herpes virus (HSV-TK) converts these drugs into intermediates capable of inhibiting DNA synthesis in vivo. Transfer of HSV-TK into tumor cells by retroviral vectors has been shown to mediate tumor regression from mouse sarcomas (Moolten & Wells, J. Natl. Cancer Inst., 82:297-300 (1990)) and to prevent growth of neoplastic BALB/c murine cell lines (Moolten, Cancer Res. 46:527-581 (1986)).
It would be advantageous to develop procedures for gene transfer via efficient vectors into cells followed by intracerebral grafting of genetically modified cells in vivo to treat brain tumors by introduction of therapeutic genes such as HSV-TK into the tumors.